ORIGINAL ARTICLE Scand J Infect Dis 28: 21-26, 1996

Hepatitis C Virus Transmission, 1988-1 991 I via Blood Components from Donors Subsequently Found to be Anti-HCV-positive ULLA FOBERG', BENGT EKERM02, ANDERS WIDELL4, ULRIK MATHIESEN3 and ARIL FRYDEN' From the Departments of 'Infectious Diseases, 'Transfusion Medicine and -'Internal Medicine, Faculty of Health Sciences, University Hospital, Linkoping, and 4Medical Microbiology, Section for Clinical Virology, Malmo General Hospital, University of Lurld, Malmo, Sweden

The recipients of blood components, from the first 12 anti-hepatitis C virus (HCV) positive donors identified by blood donor screening, 1988-1991, were traced retrospectively and tested to assess the HCV transmission rate, HCV genotypes and disease severity. Three enzyme-linked immunosorbent assay (ELISA) positive but RIBA-indeterminate and HCV RNA-neg- ative donors did not transmit HCV to their 9 traced recipients. Nine RIBA- and HCV RNA-positive donors had donated blood to 27 now living recipients of whom 16/27 (59%) were viraemic 1-5 years later. Nine recipents had resolved infection, as determined by PCR HCV RNA. Five of these were RIBA-2 positive but HCV RNA-negative and 4 recipients were RIBA-Zindeteminate and HCV RNA-negative. Two recipients negative in all tests had probably received blood before the donor became infected with HCV. The HCV genotype in each case was identical between the donor and the recipient. Of the viraemic recipients, 50% (8116) were unsuitable for further investigation or therapy due to their high age and/or underlying severe disease. At most, only 30% (8127) of the recipients were suitable for further investigation andlor treatment. Two of these were already diagnosed as being infected with HCV before being traced. It is concluded that the benefit of a general tracing of recipients of blood components from HCV-infected donors is doubtful since only a few of them are suitable candidates for treatment. Our results seem to indicate that it is more appropriate to recommend anti-HCV testing to those seeking medical care who have received transfusions or undergone major surgery before 1992, i.e. before anti-HCV-screening was initiated.

V. Foberg, MD, Department of Infectious Diseases, Faculty of Health Sciences, Linkoping University Hospital, S-58185 Linkoping, Sweden

INTRODUCTION

The major agent causing post-transfusion hepatitis (FTH), hepatitis C virus (HCV), was cloned in 1989 ( 1 , 2). This discovery was rapidly followed by the introduction of HCV antibody screening tests. Anti-HCV testing was introduced to blood donor screening in Sweden in 1990, and was mandatory by January 1992. Since then the risk of con- tracting PTH due to HCV has been greatly reduced. In order to assess ongoing infection (viraemia) the sensitive polymerase chain reaction (PCR) for detection of HCV RNA is used (3). Recent analyses of different HCV isolates (4, 5) have identified at least 6 major genotypes and several subtypes of HCV. Genotyping has been useful in epidemio- logical investigations, and may also have clinical and thera- peutic implications ( 6 , 7). In a recent study by Shev et al. (7), 4 different subtypes (la, Ib, 2b and 3a) belonging to 3 major genotypes were found among Swedish blood donors.

With the possibility of improved antiviral therapy the question has been raised whether recipients of blood com- ponents from blood donors subsequently found to be anti- HCV positive should be traced. The aims of the present study were to investigate retrospectively the HCV transmis- sion rate by transfusion of blood components from donors subsequently found to be anti-HCV-positive and to identify the chronic carriers among their recipients. HCV genotyp-

ing was performed to obtain further evidence, and indicated that donor-recipient transmission had occurred.

MATERIALS AND METHODS

Donors Since the onset of blood donor anti-HCV screening in 1990, anti-HCV-positive donors have been referred to the Department of Infectious Diseases, University Hospital Linkoping, for interview, clinical and virological evaluation. The first 12 donors, who were found to be anti-HCV-positive by second-generation anti-HCV enzyme-linked immunosorbent assay (ELISA) and positive anti- HCV-positive or indeterminate second-generation RIBA, were the index donors of this study.

Recipients All living recipients who had received blood components from these donors between 1988 and 1991 were traced. The year 1988 was chosen, since from that year onwards all transfusion data were recorded on computer.

Evaluation procedure Blood samples from all donors and recipients were tested for alanineaminotransferase ( ALT) levels using standard laboratory procedures. Sera were also tested for HBsAg, anti-HBs and anti- HBc and anti-HIV by means of commercially available im- munoassays.

The study was approved by the Committee of Ethics at Linkop- ing University.

0 1996 Scandinavian University Press. ISSN 0036-5548

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22 U. Foberg et al. Scand J Infect Dis 28

Table I. Demographic data of 9 H C V RNA-positive blood donors

Donor Age" Sex Probable mode of HCV RNA RIBA-2 (5-1-1; No. (years) (M/F) transmission genotype ClO& c,,,; c22-3)

S-ALT~ Liver ( <0.7 ukat/l) histology

42 36 46 34 26 47 43 32 29

M M F F F M F M M

IVDU Sporadic Sporadic or sexual Transferred Sporadic or sexual Transferred Transferred IVDU IVDU

2b l a l a Ib 2b 2b l b 3a l a

1 1 4 4 " 4 4 3 4 3 3 3 4 3 3 3 4 0 0 4 4 0 0 4 4 3 3 3 4 0 0 3 4 4 4 4 4

1.3 0.87 0.27 0.50 2.8 0.51 0.12 0.97 1.5

CPH CPH/fibrosis CPH NSRH CPH CPH CPH CPH nd

CPH, chronic persistent hepatitis; IVDU, intravenous drug use; nd, not done; NSRH, non-specific reactive hepatitis. a Age at diagnosis of HCV infection.

Taken at the time of liver biopsy and anti-HCV ELISA-2, RIBA-2 and PCR. I , Weak reaction; 4, strong reaction.

Anti-HCV testing Sera from donors and recipients were tested using an ELISA-2 (Ortho Diagnostic Systems Inc, Raritan, New Jersey, USA) and RIBA-2 (Chiron Corporation, Emeryville, California, USA) ac- cording to the manufacturer's instructions. Sera were stored at -20°C and during transportation were placed on dry ice.

Detection and typing of HCV RNA The presence of HCV viraemia was determined by means of a sensitive 'nested' PCR as described earlier (3) and genotyping of the HCV strains was done using type-specific primers as described recently (6).

RESULTS

Donors Between 1988 and 1991, 12 anti-HCV-positive donors do- nated 71 blood components (red cells, platelets and plasma) to 69 recipients, of whom 32 (46%) had died of underlying disease within 1 year of transfusion. The time interval between donation and transfusion of blood components was most often 1-3 weeks. In some cases, however, frozen plasma had been stored for several months. None of the donors had clinical or laboratory signs of liver disease, apart from raised ALT levels in some (Table I). All were HBsAg- and anti-HIV-negative. Three donors were positive for anti-HBc, 2 of these were also positive for anti-HBs. One was positive for anti-HBs only.

Nine of the 12 donors were RIBA-2 and HCV RNA-pos- itive. Their median age was 36 years (range 26-47 years). Clinical, epidemiological and virological data of these donors are presented in Table I.

Donors presumably infected during the study period In 2 donors, the time of HCV infection could be established accurately from hospital records. One donor (No. 5) had donated blood 13 times since 1984. She donated blood in 1988, to recipient No. 13, who was negative in all HCV tests, performed in 1992-1993. The donor was probably

infected by the sexual route during 1989- 1990. Repeatedly elevated ALT levels were observed after March 1990. A serum sample from April 1991 was anti-HCV ELISA-1- negative, but blood samples from June 1991 onwards were anti-HCV ELISA-2, RIBA-2 and HCV RNA-positive. The donor was probably infected in April 1991. Her subsequent recipient (No. 14), who was transfused in April 1991, became infected, but had resolved the HCV infection when traced (Table 11).

Donor No. 9 had given blood 3 times from 1987. He started intravenous drug use in 1989. He was probably not infected when donating blood in February 1988 to recipient No. 26 who was negative in all HCV tests, but was viraemic 16 months later when donating to recipient No. 27.

HCV RNA-negative donors Three HCV RNA-negative donors (all women) who were anti-HCV ELISA-2 positive but RIBA-2-indeterminate do- nated blood components to 10 living recipients (data miss- ing in 1 reipient) (Fig. I). Probable routes of transmission were transfusion, intravenous drug use and an unknown source of infection (1 case each).

Recipients of blood components from 9 HCV RNA-positive donors Twenty-one of 48 recipients originally exposed to blood components from the 9 viraemic donors had died within 1 year after transfusion. Thus 27 living recipients were investigated (Fig. 1, Table 11). Follow-up testing of these 27 recipients (11 men, 16 women) with a median age of 62 years (range 1 1-81 years) was done 1-5 years after transfusion. Two recipients (Nos 13 and 26) were negative in all HCV markers and had probably been transfused before the donor became infected (see above). If these 2 recipients are excluded the transmission rate amounts to 100%.

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S a n d J Infect Dis 28

Table 11. Demographic data of blood donors and recipients with HCV markers

Donor" Recipients

Hepatitis C virus transmission 1988-1991 23

Age at RIBA-2 No. transfusion Reason for HCV (5-1-1; Clm; S-ALT~

( years)/sex transfusion No. genotype c33c; c22-3) (&t/l)

1 2b 64/M Hip arthroplasty 1' Pos./2b 0 0 4 4 E 65/M Hip arthroplasty 2' Neg." 0 0 4 4 E

2 la 68/M Hip arthroplasty 3' Pos./la 0 0 4 4 E 81/F Op ovarian cancer 4' Pos./la 4 4 4 4 N 62/F Femur amputation 5 Neg. 3 0 4 0 N 73/F Knee arthroplasty 6 Pos./la 2 3 3 0 E 56/F Coronary surgery, 7' Pos./la 4 4 4 4 N

Genotype

aortic valve replacement

N 0 0 0 2 3 la 54/F Coronary surgery RA 8 Neg. 72/F Ileal obstructiond 9' Neg. ? ? 1 4 N 62/F Hip arthroplasty 10' Pos./la 4 3 4 4 E

4 lb 78/M Femur amputation 11' Pos./lb 4 4 3 4 E 53/F Subtotal pancreatectomy 12 Neg. 0 0 0 4 N

5 2b 70/F Bleeding due to anticoagulants 13 Neg." Neg." N 67/F AML 14f Neg. 0 0 0 4 N

6 2b 36/F Bleeding due to ablatio placentaed

66/M Primary HCC

1 5' Pos./2b ? ? 1 4 E

16 Pos./2b 4 4 4 4 E

7 lb 59/M Gastrectomy, cancer 17 Pos./lb 0 0 4 4 N 13/M ITP 18 Neg. 1 2 1 4 N 24/M Severe burn 19 Pos./lb 3 1 4 3 E 66/F Hysterectomy 20 Neg. 0 0 0 3 N 45/M AML, interferon treatment 21' Neg. 3 3 4 4 N 58/F Bleeding, gastric ulcer 22 Pos./lb 3 3 3 4 N

8 3a 74/F Thyroidectomy 23 Pos./3a 0 0 4 4 E 11/F Surgery for malignant 24 Pos./3a 0 0 3 4 E

56/F Hip arthroplasty 25 Pos./3a 0 1 4 4 E

9 la 65/M Surgery for malignant 26 Neg.e Neg.' N

12/M Pancytopenia/renal transplant 27' Pos./la 1 1 3 3 N

cerebral tumour

cerebral tumour

a For clinical and virological data on donors see Table I. Tested at the same time as the samples for HCV tests. E, elevated ALT; N, normal ALT. Tested on several samples. Acute hepatitis. Anti-HCV ELISA-2 negative, probably non-infectious blood. ' Diagnosis established before this study.

AML, acute myeloid leukaemia; RA, rheumatoid arthritis; HCC, hepatocellular carcinoma; ITP, idiopathic thrombocytopenic purpura.

The HCV genotype in HCV RNA-positive recipients was identical between donor and recipients, including genotypes la, lb, 2b and 3a.

Of the remaining 25 subjects, 16 (64%) were HCV RNA- positive, whereas 9 had resolved their infection as deter- mined by PCR on serum and plasma (Fig. 1). Of these viraemic recipients, 50% (8/16) never underwent liver biop- sies nor were they suitable for therapy. The reasons were

high age (recipient Nos 4, 6, 11 and 23) and/or severe underlying disease (recipient Nos 4, 16, 17, 24 and 27).

Two of the other 8 viraemic recipients refused further investigation and therapy. One patient was a 24-year-old man (No. 19) hospitalized for a long time due to severe burns. The other was a 56-year-old woman (No. 7) treated with anticoagulants following aortic valve replacement and coronary surgery. Four of the remaining 6 viraemic recipi-

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Scand J Infect Dis 28 24 U. Foberg et al.

12 anti-HCV-positive blood donors

3 HCV RNA-negative

2L _ _ - -

} -{ 1 recipienl 1 missing data 9 non-infected recipientsb) 27 recipients

6 unsuitable for unsuitable for further investigation

further investigation and therapy 1 end 11 therapy 2 refused I Fig. 1. Data of the recipients from 12 anti-HCV-positive blood donors. "RIBA-2 indeterminate. bAntiHCV-ELISA negative.

ents were already known as anti-HCV-positive before our tracing; 3 (Nos 1, 3 and 10) were found due to a prospec- tive PTH study (8) and 1 recipient (No. 15) was found due to symptomatic hepatitis.

Two viraemic recipients had not been previously investi- gated (Nos 22 and 25). Their liver histology showed slight fibrosis and chronic persistent hepatitis (CPH), respectively.

In 1 recipient (No. 2), HCV RNA performed on serum was repeatedly negative, although raised ALT levels and chronic active hepatitis with cirrhosis (CAHci) on liver biopsy was noted and confirmed anti-HCV-positive by RIBA-2. The negative HCV-RNA analyses in this case may be due to sampling problems.

Liver biopsy was performed in 7 recipients, 6 of whom were proven to be viraemic. One recipient (No. 3) had chronic active hepatitis (CAH), 1 (No. 2) had CAHci, 4 (Nos 1, 10, 15 and 25) had CPH, and 1 (No. 22) had slight fibrosis.

Five recipients had repeatedly normal ALT levels despite having HCV viraemia.

Clinical follow -up and interferon treatment Two recipients with CAH (recipient No. 3) and CAHci (recipient No. 2), respectively, were treated with interferon (IFN). Recipient No. 3 showed a partial response but continued to be viraemic following 15 months' treatment, while recipient No. 2 showed a complete sustained re- sponse.

One 36-year-old woman (recipient No. 15) who devel- oped acute hepatitis after transfusion in association with placental bleeding had CPH. She received IFN treatment for 9 months and showed complete clinical and virological response,

One recipient (No. 21) had been treated with low dose IFN for acute myeloid leukaemia. He had normal ALT

levels, positive by RIBA-2, but HCV RNA was not de- tected.

Recipients of blood components from 3 HCV RNA-negative donors Nine recipients were identified who had received compo- nents from 3 RIBA-inderterminate and HCV RNA-nega- tive donors. Sera from these 9 patients were negative for anti-HCV by ELISA-2 and RIBA-2 and negative also for HCV-RNA.

DISCUSSION

The reasons for tracing HCV-exposed recipients are at least 3-fold: (i) to find out if transmission has occurred and, if so, to follow up the infected recipients; (ii) to start therapy early to prevent development of late sequelae; and (iii) to limit secondary spread (although low) to others, i.e. family members and medical staff. So far no consensus has been drawn on whether tracing recipients of HCV-infected blood should be done or not in Sweden. In Denmark, the decision to carry out a national HCV look-back to trace recipients of HCV-infected blood has been taken, but the trace has met with practical difficulties (Per Wantzin, pers. comm.). In the UK and USA it has been stated that such tracing is not recommended since the medical benefit would be small in relation to the work required for the procedure (9). However, in a recent Scottish report by Ayob et al. (9), a reassessment of current policies on HCV tracing was sug- gested. This is mainly based on ethical grounds for the individual and a presumed future improvement in therapy. However, no analysis of the medical benefit of therapy was presented. This is also the case in a recent report from Vrielink et al. from the Netherlands (10) who also advocate HCV look-back tracing, since a high transmission rate of

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Scand J Infect Dis 28 Hepatitis C virus transmission 1988-1991 25

81% was found in the investigated recipients of blood components from viraemic donors later found to be HCV RNA-positive.

In our study the transmission rate by HCV RNA-posi- tive donors was high (93- 100% depending on whether the first non-infectious donations of 2 donors are included or not). This is in accordance with the results of recent stud- ies (1 1-14), Of infected recipients, 64% (16/25) were still viraemic 1-5 years after the transfusion, which is in agree- ment with the finding of Skaug et al., who observed a HCV carrier rate of 75% after 6 months (1 1). In a recent study from Iceland, using the same methodology as in the present study, a transmission rate of 93% was found, and 85% of the recipients were still viraemic 1-2 years after their transfusion (14). The reason for this difference may be related to different viral strains or differences in the recipient population. In the Icelandic study, all donors were found to have aquired their infection by intravenous drug use (14). Recent studies have confirmed the devel- opment of chronic hepatitis C in about 80% of the pa- tients infected by HCV either by parenteral route or sporadically, when the source of infection is unknown

Only 6 of the 25 (24%) antibody-positive recipients were suitable candidates for further investigation with liver biopsy and/or treatment (Fig. 1, Table 11). Similar results have also been obtained in a recent study by Norda et al. (16). They found 7/13 recipients to be HCV-RNA-positive after 8 months’ follow-up after transfusion. However, only 3 recipients were viraemic and suitable candidates for fur- ther investigation or treatment.

In our study, 8 viraemic recipients had severe underlying disease, high age and/or were unwilling to participate in further investigations.

IFN therapy seems to offer an initial response rate of 40-SO%, but a sustained rate of only some 20%. Recent improvements in IFN therapy, either in the form of pro- longed treatment schedules (17) or in combination with ribavirin (1 8) have led to higher sustained response rates.

In view of the late complications of HCV infection such as cirrhosis and hepatocellular carcinoma (19, 20) it seems relevant to identify recipients with HCV infection who have a long life expectancy. Even if a policy is taken to trace all recipients of donors with confirmed anti-HCV reactivity, those transfused with components from donors who have ceased to give blood before anti-HCV screening started will not be detected. The question of whether recipients exposed to HCV-infected donors should be traced or not has eco- nomical and ethical perspectives, and is by no means easy to answer.

To identify recipients of blood components from HCV- infected donors before screening started would be very time consuming. In the present study tracing of blood was facilitated by the use of computerized records. Tracing of blood donors in blood banks that have not been computer-

(15).

ized would be much more laborious. Many years have now elapsed since screening was introduced, thus markedly re- ducing the number of living recipients (10, 16, 21).

We conclude that a very high transmission rate via HCV-infected blood components was found, and that the stability of the viral genotypes was high when transmitted from donor to recipient. However, the tracing of infected recipients by HCV-infected blood components is very time consuming, causes considerable anxiety amongst the recipi- ents and relatively few of them seem to be suitable for antiviral treatment. Thus it is presently not advisable to undertake general HCV tracing. If therapy improves this strategy may have to be re-evaluated. Furthermore, the epidemiological benefit seems limited since only a few HCV-infected recipients are revealed compared to the over- all estimated number of HCV carriers (amounting to some 40,000 in Sweden). Therefore, it seems more appropriate to recommend anti-HCV-testing to all individuals seeking medical care and who have a history of blood transfusion before 1992, before anti-HCV screening started.

ACKNOWLEDGEMENTS This study was supported by grants from the County Council of hergotland, the Swedish Medical Research Council (grant 16X- 02865), Alfred 6sterlund Foundation and the Faculties of Medicine at Linkoping and Lund Universities and Schering-Plough Company. The skilful assistance of research nurse Lotta Lindvall and laboratory technician Siv Minsson is greatly acknowledged as is the reviewing of the manuscript by Associate Professor Gudrun Liedkn, Department of Transfusion Medicine, University Hospital, Linkoping.

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